This application requests a five year renewal of our study of the familial transmission of substance abuse using a combination of the family study/longitudinal high risk paradigms. The findings from the initial phase of the study demonstrate that the relatives of the substance abusing probands have a specific pattern of psychopathology and substance abuse which was also apparent in their offspring under age 18. These children also exhibited numerous abnormalities in the indirect measures of brain functioning, thereby suggesting a congenital developmental basis for their vulnerability to these conditions. Based on these findings, we propose to investigate the mechanisms for the familial aggregation of substance abuse through the following aims: (1) to analyze the patterns of familial transmission of substance abuse and comorbid disorders among the adult relatives from the family study data collected during the first project period; (2) to incorporate probands groups of alcoholics from a previous study to control for the presence of alcoholism in substance abusing probands in assessing the specificity of transmission of substance abuse, and to expand the samples of probands with substance abuse to yield sufficient power for the analyses of the children; (3) to conduct longitudinal follow-up interviews of the children to assess the stability of the assessments and investigate the early patterns of substance use and manifestations of psychopathology; (4) to integrate the assessment of environmental factors such as familial interaction to examine the joint role of familial vulnerability and interaction patterns in the etiology of substance abuse; and (5) to expand the pedigrees of the children vertically in order to examine the family constellations beyond the nuclear family in order to assess the interaction between the environmental exposure to substance abuse and degree of genetic relatedness of the subjects. Implementation of these steps should ultimately lead to the specification of vulnerable children and the risk factors on which to target prevention and intervention efforts for substance abuse.